Towards a Mouse Model of Classical Hodgkin's Disease and PTLD

Summary

Principal Investigator: FREDERICK WAYNE ALT
Abstract: DESCRIPTION (provided by applicant): In Hodgkin's Disease (HD), the most common lymphoma in the Western world, the malignant cells are the so-called Hodgkin and Reed-Sternberg (HRS) cells, comprising only a few percent of the lymphoma mass. HRS cells are often infected by Epstein-Barr-Virus (EBV) and express the EBV proteins LMP1 and LMP2A, partially mimicking constitutively an active CD40 co-receptor and B cell antigen receptor (BCR), respectively. Previous work, which had identified somatically mutated B cells, often bearing mutations "crippling" BCR expression, as HRS progenitors, led to a scenario of HD pathogenesis, in which HRS cells derive from pre-apoptotic GC B cells rescued by LMP2A and LMP1 expression. Despite their B cell origin, HRS cells have largely lost the B cell-specific gene expression program and acquired expression of genes typical for the T and/or myeloid hematopoietic lineages. We hypothesize that this lineage infidelity is dictated by the interference of certain transcription factors (TFs) known to be expressed in HRS cells, namely Id2, ABF1 and Notch1, with the B cell- specific gene expression program. This together with constitutive expression of proteins promoting cell survival and proliferation, like the TF c-Jun and TFs of the NF-kB family, may ultimately reprogram GC B cells into HRS cells. In this general scenario, EBV infection is a major initial transforming event in HD, and is indeed known to result in up-regulation of the TFs NF-kB, AP1, Id2 and ABF1 in B cells. Following this general hypothesis, we have developed a strategy to target the expression of candidate genes into GC B cells, using Cre-mediated conditional gene targeting. Using and further improving these tools, we plan to analyze whether induced expression of the various EBV-derived proteins and TFs individually and in combination in GC B cells will result in trans-differentiation and transformation of those cells as it is seen in HRS cells in HD. Our ultimate goal is to generate a mouse model of HD and to better understand the role of cellular reprogramming in lymphomagenesis. A second EBV-associated disease addressed in the present proposal is Post-Transplant Lymphoproliferative Disorder (PTLD), common in post-transplantation patients and due to a significant extent to the outgrowth of EBV-infected B cells because of immune suppression. We have found that induced expression of the EBV protein LMP1, known to be a major player in EBV-mediated B cell transformation, in developing B cells in the mouse leads to the rejection of these cells by the immune system. Depletion of T cells in the animals results in the rapid outgrowth of LMP1 expressing B cell blasts and death of the mice within a few weeks. We plan to develop this system into a first mouse model of PTLD, by targeting LMP1 expression into mature B cells, and to fully characterize disease progression and reversibility in the mutant animals, with a view of ultimately using this model for the development of new therapeutic strategies. Public Health Relevance: Hodgkin's Disease (HD) is the most common lymphoma in the Western world, and Post-Transplant Lymphoproliferative Disorder (PTLD) is an important cause of morbidity and mortality in post-transplantation patients, posing a significant clinical problem. Epstein-Barr-Virus (EBV) plays a major role in both HD and PTLD, with almost half of the HD cases and most of PTLDs being associated with it. The present proposal is based on known features of the pathogenesis of these diseases in the human and extensive own work, and aims at the generation of EBV-related mouse models of HD and PTLD, which so far do not exist, but should open the way to new therapeutic strategies and also shed new light on the role of gene expression reprogramming in lymphomagenesis.
Funding Period: 2002-12-01 - 2014-08-28
more information: NIH RePORT

Top Publications

  1. pmc Tracking germinal center B cells expressing germ-line immunoglobulin gamma1 transcripts by conditional gene targeting
    Stefano Casola
    CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 103:7396-401. 2006
  2. ncbi Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination
    Ulf Klein
    Institute for Cancer Genetics, Department of Pathology and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA
    Nat Immunol 7:773-82. 2006
  3. pmc Lymphocyte development: overview
    Klaus Rajewsky
    Curr Opin Immunol 20:127-30. 2008
  4. pmc Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model
    Baochun Zhang
    Program of Cellular and Molecular Medicine, Children s Hospital and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
    Cell 148:739-51. 2012
  5. pmc Polymorphisms in inflammation pathway genes and endometrial cancer risk
    Ryan J Delahanty
    Division of Epidemiology, Department of Medicineand Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
    Cancer Epidemiol Biomarkers Prev 22:216-23. 2013
  6. pmc Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center-derived B-cell lymphomas
    Monica Gostissa
    Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:2934-9. 2013
  7. pmc IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances
    Monica Gostissa
    Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children s Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115
    Proc Natl Acad Sci U S A 111:2644-9. 2014

Research Grants

Detail Information

Publications7

  1. pmc Tracking germinal center B cells expressing germ-line immunoglobulin gamma1 transcripts by conditional gene targeting
    Stefano Casola
    CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 103:7396-401. 2006
    ..To expedite the genetic analysis of GC B cells, we have established Cgamma1-cre F(1) embryonic stem cells, allowing further rounds of gene targeting and the cloning of compound mutants by tetraploid embryo complementation...
  2. ncbi Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination
    Ulf Klein
    Institute for Cancer Genetics, Department of Pathology and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA
    Nat Immunol 7:773-82. 2006
    ..These results identify IRF4 as a crucial transcriptional 'switch' in the generation of functionally competent plasma cells...
  3. pmc Lymphocyte development: overview
    Klaus Rajewsky
    Curr Opin Immunol 20:127-30. 2008
  4. pmc Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model
    Baochun Zhang
    Program of Cellular and Molecular Medicine, Children s Hospital and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
    Cell 148:739-51. 2012
    ....
  5. pmc Polymorphisms in inflammation pathway genes and endometrial cancer risk
    Ryan J Delahanty
    Division of Epidemiology, Department of Medicineand Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
    Cancer Epidemiol Biomarkers Prev 22:216-23. 2013
    ..Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis...
  6. pmc Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center-derived B-cell lymphomas
    Monica Gostissa
    Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:2934-9. 2013
    ..Our studies indicate that deletion of p53 is sufficient to trigger transformation of mature B cells and support the notion that p53 deficiency may allow accumulation of oncogenic translocations in B cells...
  7. pmc IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances
    Monica Gostissa
    Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children s Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115
    Proc Natl Acad Sci U S A 111:2644-9. 2014
    ..We suggest that CSR exploits a general propensity of intrachromosomal DSBs separated by several hundred kilobases to be frequently joined together and discuss the relevance of this finding for recurrent interstitial deletions in cancer. ..

Research Grants30

  1. Development of a Small Molecule Inhibitor for EBV Latent Infection
    Mark McDonnell; Fiscal Year: 2013
    ..The product being developed in this proposal is the first therapeutic small molecule drug that specifically disrupts EBV latent infection. ..
  2. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..